1. Field of the Invention
This invention relates to anticancer compositions. More specifically, the invention relates to certain 4-[3,4-dihydro-4,4-dimethyl-2H-1-benzoheterapyran-6-yl)-1-propenyl]benzoat es and derivatives thereof.
2. Description of the Prior Art
To the best knowledge of the inventors, the title compounds have not been reported in the literature but certain hydrocarbon counterparts are documented. Such hydrocarbon systems have been referred to as arotinoids and several papers on the subject have been published, such as in the European Journal of Medicinal Chemistry, 1980, Vol. 15, pages 9-15, entitled "Arotinoids, A New Class of Highly Active Retinoids" by P. Loeliger, W. Bollag and H. Mayer. Synthesis and stereochemistry are discussed. A second more recent publication has peripherally related derivatives and is entitled "Fluorinated Retinoic Acids and Their Analogues". 3. Synthesis and Biological Acitivity of Aromatic 6-Fluoro Analogues" by A. J. Lovey and B. A. Pawson. The article appeared in the Journal of Medicinal Chemistry, Vol. 25, pages 71-75 (1982). A review of the entire area of biological activity of retinoids and related compounds has been published in the Journal of Medicinal Chemistry, Vol. 25, pages 1269-1277 (1982). The title is "Retinoids at the Threshold: Their Biological Significance and Therapeutic Potential", by B. A. Pawson, C. W. Ehmann, L. M. Itri, and M. I. Sherman. The first paper contains work which is the most closely related to the compounds cited in this application in terms of preparation from ketones and conversion to the final product through a type of Wittig reaction. In no case, however, was a heteroatom ever involved in the ring systems employed and it is felt that the presence of the heteroatom makes a significant difference in the properties of the heteroarotinoids described and claimed herein.
According to the existing literature, some derivatives of the arotinoids have been found to possess useful biological activities. One type of test for therapeutic potency is the antipapilloma test (cited in the first article above) and the tracheal organ culture assay which is described in an article in the Journal of Cancer Research, Vol. 40, 3413-3425 (1980) by D. L. Newton, W. R. Henderson, and M. B. Sporn. The assays assess the ability of the test compound to prevent skin papillomas and carcinomas in mice or to prevent keratinization of cultured tracheal cells which frequently occurs when cells become premalignant. Further evidence on these points can be found in articles in entitled "Chemoprevention of Cancer with Retinoids" by M. B. Sporn and D. L. Newton, published in the Federation Proceedings, Vol. 38, pages 2528-2534 (1979) and "Structure-Activity Relationships of Retinoids in Hamster Tracheal Organ Culture" by D. L. Newton, W. R. Henderson, and M. B. Sporn, published in Cancer Research, Vol. 40, pages 3414-3425 (1980). Another test for potential anticancer activity of retinoic acid derivatives has been the ornithine decarboxylase assay which has been reviewed recently in connection with an evaluation of some aromatic retinoic acid compounds. The article is entitled "Aromatic Retinoic Acid Analogues. 2. Synthesis and Pharmacological Activity" by M. I. Dawson, R. Chan, P. D. Hobbs, W. Chao, and L. J. Schiff and was published in the Journal of Medicinal Chemistry, Vol. 26, pages 1282-1293 (1983). The compounds of the present inventions were assayed using the tracheal organ culture procedure.
The present invention novel (E)- and [(Z)]-4-[2-(3,4-dihydro-4,4-dimethyl-2H-1-benzoheterapyran-6-yl)-1-propeny l]benzoate and derivative compositions characterized by the formulae: ##STR2## where R is H, CH.sub.3, or C.sub.2 H.sub.5 and where X is S,S.fwdarw.O,O,N--CH.sub.3, Si(CH.sub.3).sub.2, N.sup.+ (H)CH.sub.3 [Cl.sup.- ], N.sup.+ (H)CH.sub.3 [Br.sup.- ], N.sup.+ (alkyl)CH.sub.3 [Br.sup.- ] and where alkyl is CH.sub.3, C.sub.2 H.sub.5, CH.sub.2 .dbd.CHCH.sub.2, or C.sub.6 H.sub.5 CH.sub.2 ; and the corresponding five-membered ring systems characterized by the formula: ##STR3## where R is H, CH.sub.3, or C.sub.2 H.sub.5 and where X is S,S.fwdarw.O,O,N,--CH.sub.3, Si(CH.sub.3).sub.2, N.sup.+ (H)CH.sub.3 (Cl.sup.- ] or N.sup.+ (H)CH.sub.3 [Br.sup.- ] or N.sup.- (H)CH.sub.3 [Cl.sup.- ], N.sup.+ (H)CH.sub.3 [Br.sup.- ], N.sup.+ (alkyl)CH.sub.3 [Cl.sup.- ] or N.sup.+ (alkyl)CH.sub.3 [Br.sup.- ] and where alkyl is CH.sub.3, C.sub.2 H.sub.5, CH.sub.2 .dbd.CHCH.sub.2 or C.sub.6 H.sub.5 CH.sub.2.
It is an object of the present invention to provide novel heteroarotinoids which are structurally related to all trans-retinoic acid and which act as anticancer agents for the treatment of skin disorders and tumors. Fulfillment of this object and the presence and fulfillment of other objects will be apparent upon complete reading of the specification and claims.